Project Summary Organic synthesis and enzymatic assays Core 1 - Ali, UMASS Medical School Drug resistance is a major limitation in the treatment of many pathogenic infections and cancers. Understanding the mechanisms of drug resistance and developing strategies to avoid resistance could lead to more effective treatments. Due to the plethora of available data, HIV-1 protease is a unique model system to study the mechanisms of drug resistance. In this highly interdisciplinary Program Project, we aim to elucidate the molecular mechanisms of drug resistance in HIV-1 protease and develop drug design strategies to avoid resistance. The Core 1 will provide medicinal chemistry support to the members of the Program Project. We will synthesize protease inhibitors and analogues required for co-crystallization, ITC, NMR, and resistance selection studies. We will work closely with the computational and structural biology groups to design new inhibitors using multiple core scaffolds that fully leverage the interdependence of different sub-sites in HIV-1 protease recognition. We will carry out the chemical synthesis of designed inhibitors and evaluate their activities in enzymatic assays against wild-type protease and drug-resistant variants. This highly collaborative and integrated approach will help elucidate the mechanisms of drug resistance and provide strategies to design more robust inhibitors less susceptible to drug resistance.